Insulin resistance in the defense against obesity

On the horizon of diabetes treatment

Q&A with LSI Director Alan Saltiel

Obesity and diabetes have reached epidemic numbers in some parts of the world, but major questions around how obesity leads to diabetes, why insulin treatment doesn’t help obesity, and how the body becomes obese in the first place still puzzle researchers.

Significant strides have been made in understanding the molecular mechanisms underlying the relationship between obesity and type 2 diabetes, and the more nuanced views of the process by which the body develops diabetes can point the way toward improved treatment of the disease.

Alan Saltiel, director of University of Michigan’s Life Sciences Institute, is a top researcher in diabetes. He challenged the conventional wisdom around the disease and suggested new ways of looking at the problem in a commentary published on June 6 in the journal Cell Metabolism.

We’ve read that there is an epidemic of obesity and diabetes in some parts of the world. Why is that?

Nobody really knows. There are a few theories: increased food availability, more sugar or other changes in diet, a more sedentary lifestyle, evolutionary pressure, viral infection, changes in the regulation of intestinal flora, low or high birth weight . . . . or some combination of all of those things. We do know that the number of people who are obese or overweight is staggering: about 1.5 billion people worldwide. It’s an epidemic, and because of the complications—like diabetes—that are associated with obesity, it’s a ticking time bomb.

Can you give us some background on what causes diabetes?

First, Types 1 and 2 diabetes are really different diseases, although they present many of the same problems regarding their awful complications, and of course both revolve around the action of the hormone insulin, which is the master regulator of blood sugar and energy metabolism in general. Type 1 diabetes usually begins in youth, and is essentially an autoimmune disease that results from destruction of the pancreatic beta cells that make insulin.

Type 2 diabetes starts when one’s response to insulin diminishes, referred to as insulin resistance. Patients make more insulin to compensate for this increased demand, until those same pancreatic insulin-producing cells eventually poop out, so that the control of blood sugar is lost.

Most patients with type 2 diabetes are obese or overweight, and when they lose weight, diabetes tends to improve. The mystery has been, what is it about obesity that leads to insulin resistance and then diabetes?

Could you explain exactly how insulin resistance occurs?

When we eat carbohydrates or proteins, the pancreas releases insulin. The insulin travels to fat, muscle and liver cells, and tells those cells to take in sugar and fat from the bloodstream. It also blocks the breakdown of that energy. . Insulin release then decreases when the level of blood sugar in your body has reached its normal level. This is called a feedback loop, which works just like the thermostat in your house or car. The whole system is rigged so that we can store energy efficiently such that it will be available when you really need it.

But chronic overeating, along with reduced activity, makes the pancreas work overtime to produce enough insulin to keep the cells absorbing all of that energy. At some point, after your cells take in as much sugar and fat as they can handle, another feedback loop kicks in, and the cells stop responding to insulin. If you think about it this way, insulin resistance is a normal homeostatic response—it’s one of the many ways the body maintains optimal function, with the right amount of energy. Not too much, not too little.

How does that explain the link between type 2 diabetes and obesity?

In the Cell Metablismcommentary I’ve proposed that there are at least four ways the body defends against obesity, and we’re beginning to understand how those defenses break down in metabolic disease. First, the cell itself tries to put the brakes on insulin’s actions when cells have adequate energy. This rheostat is a short-term and healthy response. But in the face of continued food consumption, the energy needs somewhere to go, so insulin resistance becomes systemic and sustained.

Then, another hormone, leptin, is released from fat cells when the body takes in food. This hormone binds to receptors in the brain, telling us to stop eating, and also tells the liver and fat cells to burn fat. You’d think that leptin would be a great anti-obesity agent, but experiments have proved that it doesn’t usually work because obesity is associated with leptin resistance, just like insulin resistance.

In the face of constant over-eating, fat cells continue to expand. Once leptin fails, the body’s next attempt at avoiding obesity is to deploy inflammation, which further blocks and counteracts insulin, and also tells cells to burn energy quickly. But the inflammation we see induced by obesity isn’t typical. Normally inflammation is an attack of immune cells on a wound, generated to help fight infection. The cells get in, do their jobs, and get out, a process called “resolution.” But in obesity, the inflammation is chronic and low-grade. Nothing tells the immune cells that their job is done. And they aren’t burning energy like they could.

We think that might be because inflammation is attenuated by a “counter-inflammation” response. It could be that evolutionary pressure for us to conserve energy prevents the inflammation from getting rid of fat and then resolving, like it does after an acute injury.

Nobody’s really sure what’s going on here yet, but we think we’ve identified some of the agents implicated in the “counter-inflammatory” response and maybe have found a way to interrupt it— and let inflammation do its job against excessive energy storage and obesity.

Your commentary challenges some of the conventional wisdom on diabetes. What does this mean for treating this disease?

This is an important question. For over thirty years the Holy Grail in diabetes treatment has been to find new ways to directly block insulin resistance. However, if you think about diabetes as the result of the body defending against obesity and as insulin resistance as the first line in that defense, you’d predict that blocking insulin resistance, either by trying to increase insulin action in cells or by blocking inflammation, would cause more weight gain—which is what occurs after giving insulin to patients with type 2 diabetes. I wonder whether rather than trying to fight insulin resistance, a more effective treatment might be to directly block energy storage or clear the way for more energy utilization, maybe even by blocking the counter-inflammatory events.

We’ve had some very promising findings in this area, which we’ll be publishing soon, and I hope we have the chance to find out how effective this approach is for treating diabetes.